• Information
  1. Normal Growth
  2. Short Stature
  3. Causes of Growth Hormone Deficiency
  4. Genetic Mutations and GH Deficiency
  5. Insulin-Like Growth Factor

A. Normal Growth

1. Fetal growth critical with implications for ultimate stature
2. Maximal crown-rump growth velocity is 50-60cm per year
   1. Independent of growth hormone (GH)
   2. Dependent on maternal nutrition and various other growth factors:
   3. Insulin-like (IGF 1, 2), fibroblast (FGF), epidermal (EGF), transforming (TGF) growth factors
3. Compromise in any of these factors results in intrauterine growth retardation (IUGR)
4. Post-natal growth trajectory has 3 phases: infancy, childhood, puberty
   1. Infancy: growth depends on nurtirion, some effect from GH-IGF axis at age >1 year
   2. During first 2 years of life, human height generally normalizes
   3. Height at age 3 years shows good correlation (r=0.8)
   4. By age 6, growth velocity dropps to 5-5.5cm per year (boys ~ girls)
   5. Pubertal growth depends on normal GH and sex hormone secretion
5. Correlation between progeny and parental height r=0.7
6. Ultimate average stature difference between men and women ~14 cm

B. Short Stature

1. Defined as height <2 standard deviations (SD) for age and sex matched controls
2. May also be controlled for ethnicity
3. Overview of Causes (Panel 1, Ref [1])
   1. Non-pathogenic
   2. IUGR
   3. Systemic Disorders
   4. Endocrine
   5. Chromsomal and Genetic
4. Non-Pathogenic
   1. Constitutional delay of growth and puberty
   2. Familial short stature
   3. Nutritional
5. IUGR
   1. Non-Syndromic, especially diabetes (microvascular insufficiency)
   2. Syndromic such as Silver-Russell Syndrome
6. Systemic Disorders
   1. Congenital heart disease and other cardiac disease
   2. Chronic renal insufficiency
   3. Chronic respiratory disease such as cystic fibrosis, severe asthma
   4. Gastrointestinal disease such as inflammatory bowel disease
   5. Severe neurological disease such as brain tumor
   6. Psychosocial such as anorexia nervosa, child abuse
7. Endocrine
   1. GH related diseases
   2. GH resistance
   3. Primary insulin like growth factor 1 (IGF1) deficiency [3]
   4. Hypothyroidism
   5. Glucocorticoid excess: exogenous glucocorticoids, Cushing syndrome
   6. Congenital adrenal hyperplasia (poorly managed)
8. Chromsomal and Genetic
   1. Turner's Syndrome
   2. Noonan Syndrome (see below)
   3. Down Syndrome
   4. Achondroplasia (hypochondroplasia)
   5. Spondylo-epiphyseal dysplasia
   6. Seckel syndrome
   7. Prader-Willi Syndrome
   8. Progeria
   9. Mucopolysaccharidoses
   10. Other Syndromes: Rothmund-Thompson, Leri-Weill
9. Noonan Syndrome
   1. Short stature
   2. Cardiomyopathy (variable)
   3. Valve anomalies, especially pulmonic stenosis
   4. Characteristic Facies
10. Prader-Willi Syndrome [2]
    1. Lack of expression of paternally inherited genes on chromosome 15q11-13
    2. Hyperphagia leading to obesity
    3. Short stature generally responds to GH

C. Causes of Growth Hormone Deficiency (Panel 2, Ref [1])

1. Congenital versus Acquired
2. Congenital with Structural Brain Defects
   1. Agenesis of corpus callosum
   2. Setpo-optic dysplasia
   3. Holoprosencephaly
   4. Encephalocele
   5. Hydrocephalus
3. Congenital with Midline Facial Defects
   1. Cleft lip or palate
   2. Single central incisor
4. Trauma - perinatal or postnatal
5. Infection - encephalitis, meningitis
6. Central Nerous System (CNS) Tumors
   1. craniopharyngioma
   2. Pituitary adenoma or germinoma
   3. Optic glioma
7. Hypothyroidism
8. Other
   1. Histiocytosis: Langerhan's
   2. Postcranial irradiation
   3. Postchemotherapy
   4. Pituitary infarction
   5. Neurosecretory dysfunction
   6. Psychosocial deprivation

D. Genetic Mutations and GH Deficiency [1]

1. HESX1
   1. Autosomal dominant, variable penetrance
   2. Midline forebrain, eye and pituitary defects
   3. May have combined pituitary hormone deficiency
2. SOX3
   1. X-linked
   2. Isolated GH deficiency with mental retardation
3. LHX3
   1. Recessive autosomal
   2. GH, TSH, gonadotropin deficiency, pituitary hypoplasia
   3. Corticotrophs spared
   4. Short, rigid cervical spine with restricted rotation
4. LHX4
   1. Autosomal dominant
   2. GH, TSH, cortisol deficiency
   3. Persistent craniopharyngeal canal
   4. Abnormal cerebellar tonsils
5. PROP1
   1. Autosomal recessive
   2. Highly variable GH, TSH, prolactin, gonadtropin deficiency
   3. Evolving ACTH deficiency
   4. Enlarged pituitary
6. PIT1
   1. May be dominant or recessive
   2. Varaible GH, TSH, prolactin deficiencies
   3. Anterior pituitary size varies form hypoplastic to normal
7. GH Releasing Hormone Receptor (GHRHR)
   1. Autosomal recessive
   2. Type 1B GH defiency
   3. Anterior pituitary hypoplasia
8. GH1
   1. Autosomal recessive types 1A, 1B and dominant type II
   2. GH deficiency
9. GH Insensitivity Syndrome
   1. Also called Laron syndrome
   2. Rare autosomal recessive disorder
   3. Hypoglycemia in infnacy, subsequent dysmorphism
   4. Severe childhood growth failure
   5. High concentrations of circulating GH, low basal IGF-1 and IGF binding protein 3 (IGFBP3)
   6. Mutation in GH receptors have been found
   7. STAT5B protein mutation also found in one girl with this syndrome
10. Deficiency of IGF-1 or IGF-1 receptor has also been reported

E. Insulin-Like Growth Factor (IGF) [3]

1. IGF-1 is the main mediator of growth promoting actions of GH
2. GH stimulates synthesis of IGF-1 in liver, bone and other tissues
3. Severe IGF-1 deficiency affects <10,000 children worldwide, causes severe growth failure
4. Mecasermin (Increlex®) is recombinant human IGF-1
5. Starting dose is 40-80µg/kg twice daily subcutaneously, to maximum 120µg/kg/dose
6. Studied up to 8 years
7. Main side effect is hypoglycemia in 50%, usually during first month of treatment
8. Overgrowth of fat, facial bones, kidneys has been reported
9. Contraindicated in patients with closed epiphyses
10. Has also been used successfully in children with anti-GH antibodies

References

1. Dattani M and Preece M. 2004. Lancet. 363(9425):1977
2. Holland A, Whittington J, Hinton E. 2003. Lancet. 362(9)388):989
3. Insulin-Like Growth Factor 1. 2007. Med Let. 49(1261):43